Upon exogenous expression in HeLa cells and over-expression in hippocampal neurons and glial cells, we find CNIH-2 to accumulate in the early secretory pathway with a preferential localization to the trans-Golgi complex. Just like other Golgi-resident proteins, however, CNIH-2 is not literally Golgi-resident. It cycles between the trans-Golgi and the ER compartments as demonstrated by co-segregation with β-1,4-galactosyltransferase into satellite Golgi stacks, when ER-to-Golgi transport was disturbed [30], [31]. The predominant probability of CNIH-2 localization to the Golgi complex depends on its selective export from the ER initiated by COPII coat protein complex formation [45], as interference with COPII function by co-expression of a dominant-negative Sar1 mutant redistributed CNIH-2 into the ER. Simultaneously, the increase in surface expression of co-expressed GluA receptors was abolished showing that COPII-dependent trafficking of CNIH-2 is also a prerequisite for its function in cargo transport. Thus, our results are fully consistent with a role for mammalian CNIH-2 as an ER cargo exporter: it could take up cargo proteins within the ER, mediate their preferential export by interacting with the COPII coat, then might release their
